The myelin-associated glycoprotein (MAG) is localized in the periaxonal membranes of PNS and CNS myelin sheaths where it appears to be involved in glia-axon interactions. The amount of MAG in the brains of myelin deficient rats with a severe hypomyelination of the CNS due to a sex linked mutation is reduced to 2% of the control level, and proteolipid protein (PLP) is not detected suggesting that the gene for PLP that is on the X-chromosome may be affected directly. In multiple sclerosis, MAG is reduced more than PLP or myelin basic protein in periplaque areas, and in many lesions much of the MAG is in the form of its proteolytic derivative, dMAG. Glycoconjugates sharing carbohydrate epitopes with MAG and reacting with various monoclonal antibodies such as human IgM paraproteins associated with neuropathy and HNK-1 were studied further. Newly identified 19-26K dalton glycoproteins of PNS myelin that react with these antibodies have been purified and partially characterized. Testing the antigenicity of chemically modified derivatives of the major PNS-specific glycolipid reacting with these antibodies, 3-sulfate glucuronyl paragloboside, revealed idiotypic heterogeneity among the human anti-MAG IgM paraproteins. The cat is a suitable experimental animal for investigating the pathogenicity of human anti-MAG IgM paraproteins, since it expresses each of the PNS antigens reacting with the antibodies, but experiments in cats have not provided strong evidence to suggest that the human antibodies cause the neuropathy. A high proportion of patients with IgM gammopathy and neuropathy in which the IgM does not react with MAG have paraproteins that react with other acidic glycolipids, indicating that glycolipid antigens are common in neuropathy associated with IgM gammopathy. Other antigens that have been identified include GM2, GM1 and GD3, GD1B and GT1B gangliosides. Some patients with Guillain-Barre syndrome also have high titers of antibodies reacting with acidic glycolipid antigens.